Heavy metal concentration in classroom dust samples and its relationship with childhood asthma: a study from Islamic Republic of Iran.

BACKGROUND: Classrooms are an important environment for young children as this is where they spend a large part of their time. AIMS: This study was designed to quantify the levels of heavy metals in classroom dusts in Shiraz, a city southwestern Iran. The potential association between heavy metal levels and childhood asthma was also investigated. METHODS: We selected 32 schools for collecting classroom dust samples during September-November 2016. The concentration of 10 heavy metals was measured in these dust samples by optical emission spectrometry. The diagnosis of childhood asthma was made using both the medical chart of each student and examination by an allergist. The data were analysed using SPSS, version 21.0. RESULTS: The concentration of heavy metals in classroom dust samples ranged from 7559 to 53 723.0 mg/kg (mean: 16 945.5 mg/kg) for Fe, 169.0 to 952.0 mg/kg (mean 288.9 mg/kg) for Mn, and 9.0 to 971.0 mg/kg (mean 258.8 mg/kg) for Pb. We found no correlation between heavy metals in classroom dust and childhood asthma. CONCLUSION: In comparison with studies reported elsewhere, the maximum levels of lead in our study were greater. A potential explanation for the lack of correlation with childhood asthma is the large mass of the particles, preventing them from reaching the lower airways. Nevertheless, special attention should be paid to reducing high levels of heavy metals in classroom dust in this area.

Metal-triggered conformational reorientation of a self-peptide bound to a disease-associated HLA-B*27 subtype.

Conformational changes of major histocompatibility complex (MHC) antigens have the potential to be recognized by T cells and may arise from polymorphic variation of the MHC molecule, the binding of modifying ligands, or both. Here, we investigated whether metal ions could affect allele-dependent structural variation of the two minimally distinct human leukocyte antigen (HLA)-B*27:05 and HLA-B*27:09 subtypes, which exhibit differential association with the rheumatic disease ankylosing spondylitis (AS). We employed NMR spectroscopy and X-ray crystallography coupled with ensemble refinement to study the AS-associated HLA-B*27:05 subtype and the AS-nonassociated HLA-B* 27:09 in complex with the self-peptide pVIPR (RRKWRRWHL). Both techniques revealed that pVIPR exhibits a higher degree of flexibility when complexed with HLA-B*27:05 than with HLA-B*27:09. Furthermore, we found that the binding of the metal ion Cu2+ or Ni2+, but not Mn2+, Zn2+, or Hg2+, affects the structure of a pVIPR-bound HLA-B*27 molecule in a subtype-dependent manner. In HLA-B*27:05, the metals triggered conformational reorientations of pVIPR, but no such structural changes were observed in the HLA-B*27:09 subtype, with or without bound metal ion. These observations provide the first demonstration that not only major histocompatibility complex class II, but also class I, molecules can undergo metal ion-induced conformational alterations. Our findings suggest that metals may have a role in triggering rheumatic diseases such as AS and also have implications for the molecular basis of metal-induced hypersensitivities and allergies.

Arsenic, Cadmium and Lead Exposure and Immunologic Function in Workers in Taiwan.

There has been growing concern over the impact of environmental exposure to heavy metals and other trace elements on immunologic functions. This study investigated men's arsenic (As), cadmium (Cd) and lead (Pb) contents in hair samples and their associations with immunological indicators, including white blood cell (WBC), lymphocyte and monocyte counts, and the immunoglobulin (Ig) levels including IgA, IgG and IgE. We recruited 133 men from one antimony trioxide manufacturing plant, two glass manufacturing plants and two plastics manufacturing plants. The mean concentration of Cd [0.16 (SD = 0.03) ug/g] was lower than means of As [0.86 (SD = 0.16) ug/g] and Pb [0.91 (SD = 0.22) ug/g] in hair samples, exerting no relationship with immunologic functions for Cd. The Spearman's correlation analysis showed a positive relationship between monocyte counts and hair Pb levels, but negative relations between As and IgG and between As and IgE. In conclusion, findings from these industry workers suggest that As levels in hair may have a stronger relation with immunologic function than Cd and PB have. Further research is needed to confirm the negative relationship.

The 9th Conference on Metal Toxicity and Carcinogenesis: The conference overview.

Heavy metals, such as arsenic, chromium, cadmium, nickel, mercury, and uranium are known to cause many human diseases and health complications after occupational or environmental exposure. Consequently, metals are environmental health concerns. This manuscript is an overview of the 9th Conference on Metal Toxicity and Carcinogenesis held in October 2016 in Lexington, Kentucky. Since 2000, this biennial meeting brings together experts in the field to discuss current and prospective research in an effort to advance research pertaining to metal toxicity and carcinogenesis. In this review we summarize the major topics discussed and provide insight regarding current research in the field and an account of the direction in which the field is progressing.

TLR4 (not TLR2) dominate cognate TLR activity associated with CoCrMo implant particles.

Innate immune reactions to orthopedic implant debris are the primary cause of total joint replacement (TJR) failure over the long term (15-20 years). The role of pathogen associated pattern recognition receptors (i.e., TLRs) in regulating immune reactivity to metal implant particles remains controversial. Do different TLRs (i.e., TLR2 vs. TLR4) activated by their respective ligands in concert with metal implant debris elicit equivalent innate immune responses? In this investigation, our in vitro and in vivo data indicate that Gram-negative PAMPs are more pro-inflammatory than Gram-positive PAMPs. In vitro results indicated TLR4 activation in concert with CoCrMo orthopedic implant debris (CoCrMo/LPS+) challenged primary macrophages resulted in significantly greater inflammatory responses than CoCrMo/PAM3CSK+ (TLR2). Similarly, in vivo results indicated CoCrMo/LPS+ TLR4 challenge induced a twofold increase in inflammation-induced bone resorption (osteolysis) than CoCrMo/PAM3CSK+ (p < 0.01) or CoCrMo (p < 0.03) alone in an established murine calvaria model. This points to a more potent TLR4-based effect of CoCrMo/LPS+ on innate immune responses, that is, IL-1ß, TNF-α, and resulting osteolysis. Differential CoCrMo/LPS+ induced osteolysis compared to CoCrMo/PAM3CSK+, reveals inherent differences in TLR4 versus TLR2 activation which are relevant to (i) how different types of implant debris elicit differential reactivity, (ii) how TLR2 Gram-positive bacteria benefits from less immune activation possibly due to the down-regulation of TLR2 surface expression, that subsequently impacts Gram-positive infections in TJRs, and (iii) how using TLR4 LPS (a Gram-negative agonist) may not accurately model Gram-positive bacteria responses, alone and/or with specific types of implant particles, particularly CoCrMo alloy. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1007-1017, 2017.

The role of T helper (TH)17 cells as a double-edged sword in the interplay of infection and autoimmunity with a focus on xenobiotic-induced immunomodulation.

Extensive research in recent years suggests that exposure to xenobiotic stimuli plays a critical role in autoimmunity induction and severity and that the resulting response would be exacerbated in individuals with an infection-aroused immune system. In this context, heavy metals constitute a prominent category of xenobiotic substances, known to alter divergent immune cell responses in accidentally and occupationally exposed individuals, thereby increasing the susceptibility to autoimmunity and cancer, especially when accompanied by inflammation-triggered persistent sensitization. This perception is learned from experimental models of infection and epidemiologic studies and clearly underscores the interplay of exposure to such immunomodulatory elements with pre- or postexposure infectious events. Further, the TH17 cell subset, known to be associated with a growing list of autoimmune manifestations, may be the "superstar" at the interface of xenobiotic exposure and autoimmunity. In this review, the most recently established links to this nomination are short-listed to create a framework to better understand new insights into TH17's contributions to autoimmunity.

Alteration of Th1/Th2/Th17 cytokine profile and humoral immune responses associated with chromate exposure.

BACKGROUND: The role of chromate exposure in the deregulation of total lymphocyte and other immune factors is largely unclear. OBJECTIVES: We aimed to examine alteration of the Th1/Th2/Th17 cytokine profile and humoral indicators caused by occupational chromate exposure. METHODS: A cross-sectional study was conducted in two similar workshops (groups 1 and 2) with 106 male occupational workers and 50 matched local controls. Environmental and biological exposures were assessed by measuring chromium concentrations in workplace air, and in whole blood and urine samples of the workers. Cytokines in serum (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, IL-17A) were determined by CBA assay, while immunoglobin (IgA, IgM, IgG, IgE) and complement (C3, C4) were evaluated by immunonephelometric and ELISA methods. Micronucleus analysis was also used to explore the relationship between genotoxicity and immunotoxicity. RESULTS: Compared with the control group, environmental chromate exposure in groups 1 and 2 was much higher, and the mean values of IL-6, IL-10, IFN-γ, IL-17A and IFN-γ/IL-4 were significantly decreased in group 1. In group 2, IgA and IgG levels were reduced, while C3 and C4 were increased. Levels of IFN-γ, IgG and IgA were all inversely associated with whole blood chromium, while C3 and C4 were positively associated with whole blood chromium (p<0.05). Both IL-10 and IL-17A were inversely associated with urine chromium. Correlations were also found between IL-10, IL-17A and micronucleus (r=-0.329, r=-0.312, respectively). CONCLUSIONS: Occupational exposure to chromate could downregulate the cellular and humoral factors of the immune system.

Immune responses in lactating Holstein cows supplemented with Cu, Mn, and Zn as sulfates or methionine hydroxy analogue chelates.

The aim of this study was to compare effects of inorganic sulfate versus chelated forms of supplemental Cu, Mn, and Zn on milk production, plasma and milk mineral concentrations, neutrophil activity, and antibody titer response to a model vaccination. Holstein cows (n=25) were assigned in 2 cohorts based on calving date to a 12-wk randomized complete block design study. The first cohort consisted of 17 cows that had greater days in milk (DIM; mean of 77 DIM at the start of the trial) than the second cohort of 8 cows (32 DIM at the start of the trial). Diets were formulated to supplement 100% of National Research Council requirements of Cu, Mn, and Zn by either inorganic trace minerals (ITM) in sulfate forms or chelated trace minerals (CTM) supplied as metal methionine hydroxy analog chelates, without accounting for trace mineral contribution from other dietary ingredients. Intake and milk production were recorded daily. Milk composition was measured weekly, and milk Cu, Mn, and Zn were determined at wk 0 and 8. Plasma Cu and Zn concentrations and neutrophil activity were measured at wk 0, 4, 8, and 12. Neutrophil activity was measured by in vitro assays of chemotaxis, phagocytosis, and reactive oxygen species production. A rabies vaccination was administered at wk 8, and vaccine titer response at wk 12 was measured by both rapid fluorescent focus inhibition test and ELISA. Analyzed dietary Cu was 21 and 23mg/kg, Mn was 42 and 46mg/kg, and Zn was 73 and 94mg/kg for the ITM and CTM diets, respectively. No effect of treatment was observed on milk production, milk composition, or plasma minerals. Dry matter intake was reduced for CTM compared with ITM cows, but this was largely explained by differences in body weight between treatments. Milk Cu concentration was greater for CTM than ITM cows, but this effect was limited to the earlier DIM cohort of cows and was most pronounced for multiparous compared with primiparous cows. Measures of neutrophil function were unaffected by treatment except for an enhancement in neutrophil phagocytosis with the CTM treatment found for the later DIM cohort of cows only. Rabies antibody titer in CTM cows was 2.8 fold that of ITM cows as measured by ELISA, with a trend for the rapid fluorescent focus inhibition test. Supplementation of Cu, Mn, and Zn as chelated sources may enhance immune response of early lactation dairy cows compared with cows supplemented with inorganic sources.

[Heavy metal-induced immunotoxicity and its mechanisms].

Immunotoxic effects of heavy metals, as a typical environmental agent, and their mechanisms are reviewed based on our findings on autoimmune response induced by exposure to cadmium (Cd) as CdCl(2). Adverse immune effects of chemicals, defined as immunotoxicity, have been used as a sensitive biomarker for assessing health effects of environmental chemicals. My initial research focused on renal toxicity of heavy metals was developed to elucidate characteristics and mechanisms for immune-mediated nephritis induced by heavy metals. In our studies the most interesting finding was autoantibody production enhanced by the oral exposure to Cd at environmental levels. It was observed simultaneously with enhancement of non-specific antibody production and suppression of primed-antigen specific antibody production. Immunostimulation including induction of autoantibodies was found to be the primary immunotoxic effect of Cd, because of the dose-sensitivity, and to be associated with polyclonal B cell activation (PBA). Further mechanism studies on the PBA induced by Cd in vitro showed that it was mediated by T cells, via cytokines, dominantly Type-2 cytokines, and recognition of MHC-II antigens of cell surface. The similarity among PBAs induced by inorganic salts of Cd, mercury and lead suggests that it would be the common effect among the metals to be involved in their pathogenesis of nephritis. Finally possible health significance of chemical-induced PBA is discussed associated with an increasing trend of autoimmune diseases in industrialized countries.

Patch test results with metals and meteorological conditions.

BACKGROUND: Nickel, cobalt and chromium are some of the most common causes of type IV sensitizations and subsequent allergic contact dermatitis. Accurate diagnosis of contact sensitization to these metal salts is made possible through standardized patch testing; however, patch tests with metal allergens may be influenced by meteorological conditions at the time of testing. We aimed to investigate how patch test reactions to these metals relate to outdoor temperature and humidity at the time of testing. METHODS: Clinical patch test results from 61,435 patients tested at Austrian and German dermatology departments participating in a contact sensitization surveillance network (www.ivdk.org) from 1993 through 2001 were evaluated with weather data measured near the testing location and at the time of testing. Test reactions and ambient temperature and humidity were examined with multinomial logistic regression models. RESULTS: The odds of irritant and doubtful reactions to all 3 ionized metals increased during cold/arid conditions, and the odds of weak allergic (positive) reactions to nickel and cobalt also increased during cold/dry weather. Strong allergic reactions were essentially independent of weather conditions. CONCLUSIONS: The increase in irritant and doubtful reactions coinciding with decreasing temperature and humidity may be the result of an overall increase in skin irritation brought about by these ambient conditions. The observed increases in erythematous and infiltrated ('weak allergic') reactions may be due to doubtful reactions increasing in intensity and being (falsely) classified as positive during colder and drier conditions.

Anti Zn antibodies: cross reactivity and competitive binding with heavy metals.

Monoclonal antibodies of IgM class, specific to IDA-Zn were used for evaluating their Zn(2+) binding efficiency in the presence of trace metal ions such as Cr(3+) Cr(6+), Cu(2+) and Cd(2+). In the present work, antibody raised against the hapten IDA-Zn(II) was pre-incubated with different metal ions and the binding capacity to the specific hapten was tested using ELISA and immobilized metal ion affinity chromatography (IMAC) techniques. IMAC was carried out with the free antibody and antibody pre-incubated with selected heavy metal ions using Sepharose IDA-Zn(2+) column and the same samples were tested using a hapten specific ELISA with non-protein hapten carrier. Different effects were observed after pre-incubation with metal ions. Cr(3+) exhibited synergistic binding where as antagonism was detected with Cd(2+). The synergistic effect observed with Cr(3+) suggests involvement of binding sites other than that of zinc and conformational changes that result from Cr(3+) binding. It is probable that, this binding event also increases the accessibility of the zinc binding sites on IgM. On the same lines, the antagonism observed with Cd(2+) could be attributed to structural changes resulting in reduced accessibility to zinc binding sites. In case of Cr(6+), no appreciable change in binding to IDA-Zn was observed while Cu(2+) showed competitive binding.

[Advances in heavy metal ions immunoassay].

Heavy metal leftover on farm and stock products has become a big threat to human. It is necessary to develop some fast and efficient detection methods. Heavy metal immunoassays are new methods for detection of heavy metal ions. Compared to the traditional chemical methods, immunoassays are not only fast, cheap, simple, but also reasonably portable, highly sensitive and selective. It can be used as preliminary screening for rapid determination of heavy metal ions. Except chemical chelators, phytochelatin and metallothionein can also be used for preparing immunogen, both of them can chelate heavy metal ions to carrier protein. There are two prototype assays: polyclonal antibody immunoassay and monoclonal antibody immunoassay. The former includes fluorescence polarization immunoassay; the latter includes indirectly competitive ELISA, one-step competitive immunoassay and KinExA immunoassay. Among these assays, indirectly competitive ELISA which was used for determining heavy metal ions in the early days was easy to be interfered and showed false positive. Fluorescence polarization immunoassay which used polyclonal antibody for determining heavy metal ions was simple and cheap. KinExA instrument could be functioned as an immunosensor for environmental samples. One-step immunoassay which avoided to the addition of second antibody and chromogenic substrate was simple and sensitive. Colloidal gold enhanced immunochromatography assay is a semi-quantitation for determining heavy metal ions. As an adjunctive way for chemical methods, it has the potential application in rapid determination of heavy metal ions.

[Study progress on determination of environmental trace toxicants by immunosensor].

Along with the advances in immunoassay and sensing techniques, the immunosensors based on specific immunoreaction and immobilized antibody (antigen) as recognition element were developed. They can be used for real-time, in-vivo and on-the-spot determination of pesticides, industrial organic pollutants, heavy metals, biotoxins, etc. with high sensitivity and selectivity. They possess a great potential for environmental monitoring. The working mechanism, fabrication and classification of immunosensor are briefly introduced in this paper. The latest study progress on immobilization methods and sensing techniques of immunosensor for determination of trace toxicants is reviewed. The application of immunosensor in environmental monitoring and the future development are also discussed.

[Progress on monoclonal antibody directed toward metal-chelate complexes and immunoassays to assess heavy metal contamination].

Heavy metals increase pollution on the environment. Recently, immunoassays was developed in convenience to practicability. The ELISAs and fluorescence polarization immunoassay (FPIA) based on preparation of monoclonal antibody (McAb) directed toward various heavy metal-chelate complexes may have great potential for application. Progress on McAb selective recognition metal-chelate complexes and immunoassays to assess heavy metal contaminations was reviewed in this paper.

Identification of important residues in metal-chelate recognition by monoclonal antibodies.

The molecular characterization of antibodies directed against metal-chelate complexes will provide important insights into the design and development of radiotherapeutic and radioimaging reagents. In this study, two monoclonal antibodies directed against different metal-chelate complexes were expressed as recombinant Fab fragments. Covalent modification and site-directed mutagenesis were employed to ascertain those residues important in antigen recognition. Antibody 5B2 was raised to a Pb(II)-loaded isothiocyanatobenzyl-diethylenetriamine pentaacetic acid (DTPA)-protein conjugate. The native antibody bound to complexes of Pb(II)-p-aminobenzyl-DTPA with an affinity of 4.6 x 10(-9) M. A monovalent Fab fragment prepared from the native protein and a bivalent recombinant fragment exhibited comparable affinities for the same Pb(II)-chelate complex, approximately 6-fold lower than that of the intact antibody. Covalent modification and molecular modeling predicted that Lys(58) in the heavy chain contacted the Pb(II)-chelate ligand. Mutational analysis supported a role for Lys(58) in ion pair or hydrogen bond formation with the carboxylate groups on the chelate. Antibody E5 was directed toward an isothiocyanatobenzyl-ethylenediamine tetraacetic acid (EDTA)-protein conjugate loaded with ionic Cd(II). The native immunoglobulin recognized Cd(II)-p-aminobenzyl-EDTA with an affinity of 8.2 x 10(-12) M. A proteolytically derived fragment and a bivalent recombinant fragment bound to the same Cd(II)-chelate complex with affinities that were comparable to that of the native antibody. Homology modeling and mutagenesis identified three residues (Trp(52) and His(96) in the heavy chain and Arg(96) in the light chain) that were important for Cd(II)-chelate recognition. His(96) likely mediates a direct ligation to the Cd(II) ion and Trp(52) appears to be involved in hydrophobic stacking with the benzyl moiety of the chelator. Arg(96) appeared to mediate an electrostatic or hydrogen bond to the chelate portion of the complex. These studies demonstrate that antibody recognition of metal-chelate haptens occurs through a limited number of molecular contacts and that these molecular interactions involve both direct ligation between the antibody and the metal ion and interactions between the antibody and the chelator.

[Effect of heavy metals on immune reactions in patients with infertility]. / Vliv tezkých kovu na imunitní reakci u pacientu s prokázanou neplodností.

BACKGROUND: Heavy metals can negatively influence reproduction because in sensitive persons they are able to alter the immune reactions including autoantibodies production. The altered immune reaction can then cause infertility. METHODS AND RESULTS: The in vitro lymphocyte reaction after stimulation with metals, the production of interferon (IFN-gamma) and antisperm antibodies in supernatants after lymphocyte stimulation in patients with infertility and with the antisperm antibodies present in their serum were investigated. The cause of antisperm antibodies presence was not determined. The diagnosis of metal intolerance was performed by the proliferation method modified for metals (Melisa). In supernatants of tissue cultures of lymphocytes without the antigen stimulation and after stimulation with mercury chloride, the in vitro production of gamma interferon and antisperm antibodies was studied by Elisa. More than 50% of patients did not tolerate mercury, iron, aluminium and silver. When the lymphocyte reaction was compared in patients with and without mercury intolerance we found that lymphocytes of patients with mercury intolerance produced less gamma interferon and more antisperm antibodies in supernatants after mercury stimulation of lymphocytes. CONCLUSIONS: In patients with metal intolerance diagnosed by the Melisa test, metal ions released from the dental materials can represent a factor, that does not cause infertility but is able to influence it negatively.

Effects of heavy metal ions on resting and antigen-activated CD4(+) T cells.

Heavy metal environmental pollutants increase susceptibility of affected individuals to bacterial and viral infections, but the mechanisms responsible for this effect are not known. We established cellular in vitro systems to identify molecular targets for the action of heavy metal ions. We used two model systems to determine the effects of heavy metal ions on antigen-induced T lymphocyte responses. The first system was representative of primary antigen responses and utilized CD4(+) primary T lymphocytes derived from DO.11.10 T cell receptor transgenic mice. The second system represented a memory T cell phenotype and utilized the CD4(+) T helper 1 clone, pGL2. We measured the effects of the four heavy metals cadmium, lead, mercury, and vanadium on cytokine and proliferation responses by purified CD4(+) T cell to antigenic stimulation. Cytokine responses were differentially affected by lead and vanadium at concentrations that did not affect T cell proliferation in response to antigen. We also determined whether the metal ions induced apoptotic cell death. Mercury induced apoptosis at concentrations as low as 0.5 microM, whereas cadmium required a concentration of 100 microM. Lead (maximal concentration tested was 200 microM) and vanadium (100 microM) did not induce apoptosis. The results suggested that the different heavy metal ions differentially affected antigen-stimulated responses in T helper cells. These in vitro systems can now be applied to test whether heavy metal ions alter antigen-induced T cell signal transduction pathways in CD4(+) T helper cells.

Induction of autoimmunity through bystander effects. Lessons from immunological disorders induced by heavy metals.

Autoreactive T cells exist in healthy individuals and represent a potential reservoir of pathogenic effectors which, when stimulated by microbial adjuvants, could trigger an autoimmune disease. Experimental studies have indicated that xenobiotics, well defined from a chemical point of view, could promote the differentiation of autoreactive T cells towards a pathogenic pathway. It is therefore theoretically possible that compounds present in vaccines such as thiomersal or aluminium hydroxyde can trigger autoimmune reactions through bystander effects. Mercury and gold in rodents can induce immunological disorders with autoimmune reactions. In vitro, both activate signal transduction pathways that result in the expression of cytokines, particularly of IL-4 and IFNgamma. In a suitable microenvironment heavy metals could therefore favour the activation of autoreactive T cells. In that respect, genetic background is of major importance. Genome-wide searches in the rat have shown that overlapping chromosomal regions control the immunological disorders induced by gold salt treatment, the development of experimental autoimmune encephalomyelitis and the CD45RC(high)/CD45RC(low)CD4(+)T cells balance. The identification and functional characterization of genes controlling these phenotypes may shed light on key regulatory mechanisms of immune responses. This should help to improve efficacy and safety of vaccines.

Immunotoxicity in invertebrates: measurement and ecotoxicological relevance.

Concern is growing regarding the impact of chemicals suspected of altering the function of the immune system in humans and wildlife. There are numerous examples of links between pollution and increased susceptibility to disease in wildlife species, including immunosuppression in harbour seals feeding on fish from contaminated sites, altered immune function in riverine fish and decreased host resistance in birds exposed to pollutants. Laboratory tests have identified potential immunological hazards posed by a range of anthropogenic chemicals in mammals and higher vertebrates. However, few reports have considered the ecological relevance of pollution-induced immunosuppression in invertebrate phyla, which constitute around 95% of all animal species and occupy key structural and functional roles in ecosystems. In this paper effects of chemicals on immune function in invertebrates are briefly reviewed and biomarkers of immunotoxicity are identified. Examples of new approaches for the measurement of immunological inflammatory reactions and stress in molluscan haemocytes are detailed. The relevance of defining the immune system as a target organ of toxicity in invertebrates is discussed and an integrated approach for the use of immunological biomarkers in environment management is proposed, combining measures of immune function and organismal viability at the biochemical, cellular and population level.

Murine mercury-induced autoimmunity: a model of chemically related autoimmunity in humans.

Human exposure to certain compounds or therapeutic drugs can result in the development of an autoimmune syndrome. Mercury (Hg) induced autoimmunity is one of the few animal models in which administration of a chemical induces a specific loss of tolerance to self-antigens. After receiving subtoxic doses of Hg or other heavy metals, susceptible mouse strains rapidly develop highly specific antibodies to nucleolar antigens. In addition, these animals display a general activation of the immune system, especially pronounced for the Th2 subset and a transient glomerulonephritis with immunoglobulin deposits. Like many human autoimmune diseases, this syndrome is associated with the expression of susceptible major histocompatibility complex (MHC) class II genes. In this article, we review the essential features of this model, and we discuss the putative mechanisms by which Hg creates such a severe immune dysfunction.